Surgeon-Performed Point-of-Care Ultrasound in the Diagnosis of Acute Sigmoid Diverticulitis: A Pragmatic Prospective Multicenter Cohort Study.

Background and purpose Early diagnosis and risk stratification of sigmoid diverticulitis rely heavily on timely imaging. Computerized tomography (CT), the gold standard diagnostic test, may be delayed due to resource constraints or patient comorbidity. Point-of-care ultrasound (POCUS) has an established role in trauma evaluation, and could potentially diagnose and stage acute diverticulitis, thus shortening the time to definitive treatment.  Aims This study aimed to benchmark the accuracy of surgeon-performed POCUS against CT in diagnosing and staging acute diverticulitis. A secondary aim was to evaluate the duration between the POCUS and the confirmatory CT scan report. Patients and methods A pragmatic prospective multicenter cohort study (ClinicalTrials.gov Identifier: NCT02682368) was conducted. Surgeons performed point-of-care ultrasound as first-line imaging for suspected acute diverticulitis. POCUS diagnosis and radiologic Hinchey classification were compared to CT as the reference standard. Results Of 45 patients with suspected acute diverticulitis, POCUS classified 37 (82.2%) as uncomplicated diverticulitis, four (8.8%) as complicated diverticulitis, and four (8.8%) as other diagnoses. The POCUS-estimated modified radiologic Hinchey classification was largely concordant with CT staging with an accuracy of 88.8% (95% CI, 75.95-96.2%), a sensitivity of 100% (95% CI, 90.2- 100%) and a specificity of 44.4% (95% CI, 13.7-78.8%). The positive predictive value (PPV) was 87.8% and the negative predictive value (NPV) was 100%. There was moderate agreement between CT and POCUS, with a Cohen's kappa coefficient of 0.56. The mean delay between CT and POCUS was 9.14 hours (range 0.33 to 43.5). Conclusion We examined the role of POCUS in the management of acute diverticulitis and our findings suggest that it is a promising imaging modality with the potential to reduce radiation exposure and treatment delays. Adding a POCUS training module to the surgical curriculum could enhance diagnosis and expedite the management of acute diverticulitis.

A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer.

BACKGROUND: miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. METHODS: RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq). RESULTS: miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy. CONCLUSIONS: A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.

Correction to: Surgeon-performed point-of-care ultrasound for acute cholecystitis: indications and limitations: a European Society for Trauma and Emergency Surgery (ESTES) consensus statement.

Unfortunately, the author Luca Ponchietti was omitted in the original publication. Please find the correct author list here.

Surgeon-performed point-of-care ultrasound for acute cholecystitis: indications and limitations: a European Society for Trauma and Emergency Surgery (ESTES) consensus statement.

BACKGROUND: Acute cholecystitis (AC), frequently responsible for presentation to the emergency department, requires expedient diagnosis and definitive treatment by a general surgeon. Ultrasonography, usually performed by radiology technicians and reported by radiologists, is the first-line imaging study for the assessment of AC. Targeted point-of-care ultrasound (POCUS), particularly in the hands of the treating surgeon, may represent an evolution in surgical decision-making and may expedite care, reducing morbidity and cost. METHODS: This consensus guideline was written under the auspices of the European Society of Trauma and Emergency Surgery (ESTES) by the POCUS working group. A systematic literature search identified relevant papers on the diagnosis and treatment of AC. Literature was critically-appraised according to the GRADE evidence-based guideline development method. Following a consensus conference at the European Congress of Trauma & Emergency Surgery (Valencia, Spain, May 2018), final recommendations were approved by the working group, using a modified e-Delphi process, and taking into account the level of evidence of the conclusion. RECOMMENDATIONS: We strongly recommend the use of ultrasound as the first-line imaging investigation for the diagnosis of AC; specifically, we recommend that POCUS may be adopted as the primary imaging adjunct to surgeon-performed assessment of the patient with suspected AC. In line with the Tokyo guidelines, we strongly recommend Murphy's sign, in conjunction with the presence of gallstones and/or wall thickening as diagnostic of AC in the correct clinical context. We conditionally recommend US as a preoperative predictor of difficulty of cholecystectomy. There is insufficient evidence to recommend contrast-enhanced ultrasound or Doppler ultrasonography in the diagnosis of AC. We conditionally recommend the use of ultrasound to guide percutaneous cholecystostomy placement by appropriately-trained practitioners. CONCLUSIONS: Surgeons have recently embraced POCUS to expedite diagnosis of AC and provide rapid decision-making and early treatment, streamlining the patient pathway and thereby reducing costs and morbidity.

The impossible gallbladder: aspiration as an alternative to conversion.

BACKGROUND: Laparoscopic cholecystectomy is the standard of care for symptomatic gallstone disease but when laparoscopic removal proves impossible the standard advice is to convert to open surgery. This jettisons the advantages of laparoscopy for a procedure which surgeons no longer perform routinely, so it may no longer be the safest practice. We hypothesised that gallbladder aspiration would be a safer alternative when laparoscopic removal is impossible. METHODS: A retrospective analysis was performed of all laparoscopic cholecystectomies attempted under one surgeon's care over 19 years, and the outcomes of gallbladder aspiration were compared with the standard conversion-to-open procedure within the same institution. RESULTS: Of 757 laparoscopic cholecystectomies attempted, 714 (94.3%) were successful, while 40 (5.3%) were impossible laparoscopically and underwent gallbladder aspiration. Interval cholecystectomy was later performed in 34/40 (85%). Only 3/757 (0.4%) were converted to open. No aspiration-related complications occurred and excessive bile leakage from the gallbladder was not observed. During this time 1209 laparoscopic cholecystectomies were attempted by other surgeons in the institution of which 55 (4.55%) were converted to open and 22 (40%) had procedure-associated complications. There was a significant difference in the mean (± SEM) post-operative hospital stay between laparoscopic gallbladder aspiration [3.12 (± 0.558) days] and institutional conversion-to-open cholecystectomy [9.38 (± 1.04) days] (p < 0.001), with attendant cost savings. CONCLUSION: Laparoscopic gallbladder aspiration is a safe alternative to conversion when inflammation makes cholecystectomy impossible laparoscopically, especially in the sickest patients and for surgeons with limited open surgery experience. This approach minimises morbidity and permits laparoscopic cholecystectomy in the majority after a suitable interval or referral of predicted difficult cases to specialist hepatobiliary centres.

Endocan serum concentration in uninfected newborn infants.

INTRODUCTION: Endocan is a specific endothelial mediator involved in the inflammatory response. Its role in the diagnosis of sepsis has been studied in adult patients and late onset neonatal sepsis. The clinical signs of early onset sepsis (EOS) are nonspecific and routinely used biomarkers, such as C-reactive protein and procalcitonin, have low sensitivity, specificity and positive predictive value. Endocan could be useful as a biomarker for diagnosis of EOS, but at present normal range values for this molecule have not been reported. The aim of this study is to establish the normal values range for serum endocan in term and preterm newborns without risk factors for EOS and to characterize the variation pattern of its levels at different postnatal moments. METHODOLOGY: Mean endocan serum concentration (ESC) was measured in term and preterm newborns without clinical suspicion of EOS at different moments from birth. RESULTS: ESC (ng/mL) in term newborns was 1.74+/-0.13 on day 1 and 2.02+/-0.41 on day 3 respectively, (p=0.09). In preterm newborns ESC (ng/mL) was 2.02+/-0.11 and 1.97+/-0.18, (p=0.8) for day 1 and 3 respectively. ESC was not significantly influenced by sex, mode of delivery, evidence of fetal distress or presence of minor birth trauma. CONCLUSIONS: ESC (ng/mL) between the first and third day of life in either term or preterm infants don't appear to be significantly influenced by factors that are associated with elevation of inflammatory markers, thus using this biomarker for the diagnosis of EOS might reduce the false positive results.

What's in Metabolomics for Alcoholic Liver Disease?

BACKGROUND AND AIMS: Current management of alcoholic liver disease (ALD), especially for alcoholic hepatitis (AH) is still driven by liver biopsy. Therefore, the identification of novel and accurate noninvasive biomarkers for the diagnosis and assessment of severity is important. Metabolomics, because it unravels changes closest to the phenotype, may represent the key for novel biomarkers. The aim of this study was to identify and characterize potential metabolomic biomarkers for diagnosis, staging and severity assessment of ALD. METHODS: 30 consecutive ALD patients and 10 healthy controls were included in this proof-of-concept cross-sectional study. Baseline assessment consisted in evaluation of Maddrey's Discriminant Function, Model for End-Stage Liver Disease (MELD) and ABIC scores as well as ASH-Test (Fibromax) as a surrogate for the confirmatory diagnosis of AH in suggestive clinical and biologic settings. Additionally, SOP metabolomics and lipidomics were performed from serum samples by liquid chromatography mass-spectrometry analysis. RESULTS: From the 127 and 135 serum/urine candidate metabolites initially identified, only 11/5 metabolites were characteristic for ALD patients. None of them correlated with alcohol intake, and only 5/1 metabolites could differentiate cirrhotic from non-cirrhotic patients. Of those, N-Lauroglycine (NLG) was the best for identifying cirrhosis (100% sensitivity and 90% negative predictive value, NPV) and decatrienoic acid (DTEA) was the best for assessing disease severity (evaluated by ABIC score) with 100% sensitivity and 100% NPV. CONCLUSION: Due to their high NPV, NLG and DTEA could be used in conjunction in ALD patients to exclude cirrhosis or a severe disease. If further validated, they could become biomarkers for better management and risk assessment in ALD.

Method for organically bound tritium analysis from sediment using a combustion bomb.

The method consisted in combustion, using a Parr bomb type 1121, of a sediment - tritium free promoter mixture. The proper ratio sediment to promoter in our experiments was between 1:3 and 1:2, higher ratio resulting in unreliable results, due to incomplete combustion of the sample. The described method was used to measure the estuarine sediment sample from the 2nd International OBT Intercomparison Exercise, the average reported value being 163±12Bqkg-1 dry matter (k=2).

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non-Small Cell Lung Cancer Patients (SAKK 19/05 trial).

PURPOSE: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. RESULTS: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). CONCLUSIONS: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.

Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents.

BACKGROUND: The ß-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. METHODS: The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. RESULTS: Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. CONCLUSIONS: Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis.

PURPOSE: Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis. METHODS: The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis. RESULTS: At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%). CONCLUSION: In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.

Kinetics of soluble mesothelin in patients with malignant pleural mesothelioma during treatment.

RATIONALE: Previous data suggested that serum levels of soluble mesothelin (SM) are related to tumor size and may have prognostic significance in malignant pleural mesothelioma (MPM). OBJECTIVES: We tested the hypothesis that this marker could also be useful for monitoring response to treatment. METHODS: Serial measurements of SM were determined in 40 patients diagnosed with MPM and subjected to gene-transfer therapy using intrapleural infusion of an adenoviral vector expressing human IFN-beta or conventional treatment (mainly chemotherapy). MEASUREMENTS AND MAIN RESULTS: In patients with baseline SM levels greater than 1 nM/L and disease progression after therapy, SM levels increased by 2.1 nM/L at two, 5.2 nM/L at four and 1.3 nM/L at 6 months. Patients with initial SM below 1 nM/L had a similar but more moderate increase of SM over time. Patients who responded to treatment or were considered stable had an initial small decrease of SM followed by a return to baseline values after 6 months of follow-up. In patients with baseline SM levels greater than 1 nM/L, increasing levels were associated with a significantly shorter median survival than in patients with stable or decreasing SM levels (4.4 vs. 27.7 months; P = 0.012). CONCLUSIONS: Increasing serum levels of SM were associated with disease progression and worse outcome, whereas stable or decreasing values suggested response to treatment. If confirmed in larger series, SM could be used to monitor patients with malignant pleural mesothelioma under treatment.

Accuracy of clinical presentation for differentiating bacterial from viral meningitis in adults: a multivariate approach.

OBJECTIVE: To determine whether bacterial (BM) and viral (VM) meningitis can be differentiated based on initial clinical presentation. DESIGN AND SETTING: Retrospective cohort study in a medical emergency department and intensive care unit in a university hospital. PATIENTS: 144 adults, including 90 with confirmed BM and 54 unpretreated VM. MEASUREMENTS AND RESULTS: Symptoms, examination findings, paraclinical data, and clinical outcome were assessed. Severity was defined by the presence at referral of one of the following criteria: altered consciousness, seizures, focal neurological findings, and shock. After univariate analyses we performed stepwise logistic regression to determine predictors for BM available at referral (except for CSF Gram stain) and logistic regression using previously validated CSF cutoffs. Univariate methods identified the presence of one sign of severity as the most important predictor for BM (sensitivity 0.989, specificity 0.981, positive predictive value 0.989, negative predictive value 0.981, odds ratio 4,770) and showed that CSF results differ in BM and in VM (except for CSF glucose). Logistic regression analysis revealed severity and CSF absolute neutrophil count as the two predictors of BM (R2=0.876). Logistic analysis showed that BM was related to severity (beta=6.46+/-1.27) and a CSF absolute neutrophil count above 1,000/mm3 whereas CSF glucose below 2 mmol/l and CSF protein higher than 2 g/l were not predictive. CONCLUSIONS: The presence of at least one sign of severity at referral and a CSF absolute neutrophil count above 1,000/mm3 mm are predictive of BM.

Color Doppler of the splenic artery in the prenatal diagnosis of heterotaxic syndromes.

The objective of this paper is to determine whether color and pulsed Doppler of the splenic artery is helpful in the prenatal diagnosis of polysplenia or asplenia in heterotaxic syndromes. Over a 3-year period, localization of the splenic artery by color and pulsed Doppler was attempted on all fetuses with the diagnosis of heterotaxic syndromes. Postnatal follow-up was obtained on all neonates. The diagnosis of heterotaxic syndromes was performed on eight fetuses during the study period. Mean gestational age at diagnosis was 20.1 weeks. All fetuses had situs ambiguous and complex cardiac abnormalities. All pregnancies were managed expectantly and none were terminated. The splenic artery was imaged by color and pulsed Doppler in 6 of 8 fetuses, all with one or multiple spleens confirmed postnatally. The splenic artery could not be imaged in two fetuses, both with asplenia confirmed postnatally. The perinatal mortality rate was 88% (7 of 8) and the one surviving infant is currently alive and well at 3 years of age. Color and pulsed Doppler of the splenic artery can aid in the prenatal diagnosis of heterotaxic syndromes. This information is of value and should result in improved prenatal counseling and management of affected pregnancies.

Doppler flow velocimetry of the splenic artery in the human fetus: is it a marker of chronic hypoxia?

OBJECTIVE: The aim of this investigation was to describe splenic artery flow velocity waveforms in the appropriate- and small-for-gestational-age human fetus. STUDY DESIGN: Splenic artery flow velocity waveforms were prospectively obtained from 95 appropriate- and 15 small-for-gestational-age fetuses with pulsed Doppler ultrasonography. The resistance index was used to quantify the Doppler waveform. RESULTS: A second-degree polynomial model expressed the changes of the resistance index in appropriate-for-gestational-age fetuses with advancing gestation (y = 0.057x [Weeks] - 0.001x2, r = 0.53, p < 0.001). In 14 of 15 (93%) small-for-gestational-age fetuses the splenic artery resistance index was below the mean for gestational age. In five of 15 (33%) small-for-gestational-age fetuses the resistance index of the splenic artery was < 2 SEMs. A trend toward a higher hematocrit was noted in the five fetuses with splenic artery resistance index values < 2 SEMs (50.2%) compared with other small-for-gestational-age fetuses (43.0%). CONCLUSION: Our results suggest that some small-for-gestational-age fetuses have decreased resistance at the level of the splenic artery. We postulate that the increased erythropoietin level, stimulated by hypoxia, results in decreased resistance at the level of the splenic artery in small-for-gestational-age fetuses. Finally, management of the small-for-gestational-age fetus may be aided by the study of the splenic artery waveforms.